title: Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease.
abstract: Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a key enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or 'degradome' of MMP-9 and found many systemic autoantigens as novel intracellular gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6(lpr/lpr) mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced lymphadenopathy and splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of 'double negative' T cells, B cells and myeloid cells. In addition, higher autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE autoantigens U1snRNP A and ribosomal protein P0 were hardly recognized by plasma samples of both B6(lpr/lpr).MMP-9⁻/⁻ and B6(lpr/lpr).MMP-9+/+ mice, pointing to a destruction of B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of MMP inhibitors in autoimmune lymphoproliferative syndrome (ALPS) and SLE.
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Cauwe
authors.forename: Erik
authors.initials: E
authors.lastname: Martens
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Chris
authors.initials: C
authors.lastname: Dillen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Geurts
authors.forename: Sandra
authors.initials: S
authors.lastname: Li
authors.forename: Jan
authors.initials: J
authors.lastname: Mertens
authors.forename: Greet
authors.initials: G
authors.lastname: Thijs
authors.forename: Philippe E
authors.initials: PE
authors.lastname: Van den Steen
authors.forename: Hubertine
authors.initials: H
authors.lastname: Heremans
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Daniel
authors.initials: D
authors.lastname: Blockmans
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D015551:Autoimmunity; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology*; D008232:Lymphoproliferative Disorders / Q000209:etiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr
chemical_list: D018985:Epitopes, B-Lymphocyte; D020780:Matrix Metalloproteinase 9